Efficient preparation of compound (5) of the above Reaction Scheme 1 is critical for an economical production of a fluoroquinolone-based antibiotic used for the treatment of microbial infection. A prior process known in JP Laid-Open Hei 3-74231 prepares compound (5) through the following three steps:
Step 1: 3-(2,6-Dichloro-5-fluoropyridin-3-yl)-3-oxopropanoic acid ethyl ester is reacted with triethyl orthoformate and acetic anhydride to prepare 2-[(2,6-dichloro-5-fluoropyridin-3-yl)carbonyl]-3-ethoxy acrylic acid ethyl ester;
Step 2: thus obtained compound is reacted with cyclopropylamine, and
Step 3: the resulting cyclopropyl enamine is cyclized by sodium hydride to prepare naphthyridine ester.
However, in this process, the intermediates are separated at each step, and so the whole operation is complicated and resulted in low yield.
Another process to prepare compound (5) has been described in JP Laid-Open 2002-155081. This process improves the above process described in JP Laid-Open Hei 3-74231 which is carried out the above steps 1 to 3 in the same solvent without any intermediate isolation process. This invention may be illustrated in more detail in the following three steps:
Step 1: Compound (1) is reacted with triethyl orthoformate by heating in the presence of acetic anhydride with concomitant removal of the by-products, ethanol and acetic acid. After the completion of the reaction, the residual triethyl orthoformate should be completely distilled off under reduced pressure to prevent the formation of side product in the next step.
Step 2: Thus obtained residue is cooled and dissolved in toluene. To this solution is added dropwise cyclopropylamine to prepare the enamine compound.
Step 3: Finally, a catalytic amount of tetrabutylammonium bromide is added to the solution of the enamine compound, and then aqueous sodium hydroxide solution is added to cyclize. The crystallized naphthyridine 3-carboxylic ester is filtered, washed, and dried and subsequently hydrolyzed to give compound (5) in the overall yield of about 85%.
This process is advantageous in preparing the naphthyridine ester without intermediates isolation, but also has the following disadvantage.
The reaction of Step 1 is already known in a number of references, and is a widely used as a general method (cf: WO 89/06649, EP 0 160 578 A1). However, this step has a couple of problems in an industrial aspect. First, after completion of the reaction, triethyl orthobromate should be removed thoroughly through distillation under reduced pressure. This process takes a long time. Second, if the triethyl orthoformate is not completely removed, the residual triethyl orthoformate reacts with cyclopropylamine introduced in the next step to form by-products that is difficult to purify.